Fearful symmetry: subversion of asymmetric division in cancer development and progression

Abstract

Asymmetric division is an evolutionarily conserved process that generates daughter cells with different fates through the unequal partitioning of fate determinants. While asymmetric division is critically important in generating diversity during development, its dysregulation can also promote oncogenesis. In particular, signals that shift the normal balance of symmetric and asymmetric division can lead to a differentiation arrest and trigger cancer progression. Here, we discuss the studies that have provided increasing support for this idea. Beginning with original work carried out in Drosophila, we trace more recent work in mammalian systems that suggest that the subversion of asymmetric division can contribute significantly to the development and progression of both hematologic malignancies and solid cancers.

Figure 1

Top: Basic motif of asymmetric division in normal development. The apical localization of aPKC in the dividing stem cell promotes asymmetric distribution of fate determinants such as Numb and Brat. Subsequent inheritance of the fate determinants into one daughter directs a differentiated fate (purple). Middle, Bottom: Subversion of asymmetric division during oncogenesis. Balanced symmetric and asymmetric divisions allow maintenance of cancer stem cell populations and create heterogeneity during the chronic phase or low grade. In these cancers, the maintenance of Numb and p53 levels allows continued differentiation (middle). Accrual of additional mutations results in increased symmetric renewal divisions leading to a more undifferentiated and malignant state. This is associated with elevated expression of stem cell genes such as Notch, Msi and β-catenin (bottom).